The purpose of the proposed study is to investigate whether thrombin, plasmin, and activated Factor B (Bb), (the pivotal serine proteases of the coagulation, fibrinolysis, and complement systems, respectively) and their cofactors (Factor Va and C3B) can function as an integrated system in blood. Reciprocal mechanisms of activation may exist which would allow for the activation of zymogens in one system by the active enzymes of another system. The cleavage products of prothrombin, plasminogen, and Factor B generated by activated enzymes of the opposing two systems will be investigated physically, to determine their size and chain composition, and biologically, to determine their activity in the three systems. Requirements for surfaces and protein cofactors will be investigated to determine, if components of one system may promote the cleavage mediated by an enzyme in another system. Hybrid-forms of complexes composed of an enzyme and a cofactor from different systems will be analyzed for associations as well as activity for the enzyme-cofactor mixture by activation of the zymogens in the three systems. Further, the ability of purified plasma protease-inhibitors to regulate such "hybrid"-activation complexes will be examined. Interacting factors from the respective systems will be tested to determine whether they physically association. The host inflammatory response is a composite derived from the physiological consequences of activasting coagulation, fibrinolysis, complement, and the cellular element in blood. The proposed study will allow for a determination of the molecular interactions which may occur between these respective systems. It is significant that disseminated intravscular coagulation, delayed-type hypersensitivity reactions. glomerular nephritis, allograft rejection, and tumor rejection all exhibit common pathologic features suggesting the activation of these respective blood systems. Significant new results are presented which point out the feasibility of the proposed study, and the recent development of routine techniuqes for the purification of coagulation, fibrinolytic, and complement proteins makes it possible for the first time to investigate whether interrelationships exist among these systems under physiological conditions. The possibility that the coagulation, fibrinolytic, and complement systems may exist as an integrated system of proteins on the surface of cellular elements in blood must be considered.